Several hypotheses have been suggested in the literature to explain the early ventilatory overshoot and subsequent adaptation occurring during prolonged CO2 exposure. No systematic study, however, has been done to examine the major hypotheses simultaneously. This proposal aims to establish the pattern of ventilatory adaptation to normoxic and hypoxic hypercapnia in the rat. At the same time, possible mechanisms which affect ventilation during prolonged hypercapnia will be investigated. Possible mechanisms and their measurements are as follows: (1) Arterial, cerebrospinal fluid, and brain intracellular acid-base parameters will be determined, and brain interstitial fluid acid-base values will be estimated. (2) Changes in sensitivity of the respiratory center will be detected by measuring central respiratory drive, defined as the tidal volume-to-inspiratory period ratio. This drive at a fixed stimulus will be defined as "central sensitivity" since CO2 acts mainly on central chemoreceptors. (3) Changes in lung mechanics during prolonged CO2 breathing will be studied by obtaining lung pressure-volume curves and pulmonary resistance. (4) Variation in respiratory dead space in prolonged hypercapnia will be estimated from measured ventilation, arterial and alveolar CO2 tensions. The relation between ventilation and cerebral blood flow, O2 consumption, vagal tone, as well as ammonia will also be examined. Total clearance of inhaled CO2 has been observed in man, ponies, and the rat during acute low CO2 breathing. This project further plans to study whether this CO2 clearance relates to vagally mediated afferent input from the lung and whether chronic low CO2 exposure can affect CO2 clearance.